Integrated analyses of growth differentiation factor-15 concentration and cardiometabolic diseases in humans
| Autor: | Eleanor M Wigmore, Susanna Lemmelä, Christian Benner, Aki S Havulinna, Rachel MY Ong, Tibor Kempf, Kai C Wollert, Stefan Blankenberg, Tanja Zeller, James E Peters, Veikko Salomaa, Maria Fritsch, Ruth March, Aarno Palotie, Mark Daly, Adam S Butterworth, Mervi Kinnunen, Dirk S Paul, Athena Matakidou |
|---|---|
| Přispěvatelé: | Lemmelä, Susanna [0000-0001-6027-8715], Wigmore, Eleanor M [0000-0003-0864-9990], Havulinna, Aki S [0000-0002-4787-8959], Peters, James E [0000-0002-9415-3440], Paul, Dirk S [0000-0002-8230-0116], Apollo - University of Cambridge Repository, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, University of Helsinki, Samuli Olli Ripatti / Principal Investigator, Medicum, Complex Disease Genetics, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator |
| Rok vydání: | 2022 |
| Předmět: |
BIOMARKER
obesity causality WEIGHT-LOSS global health GENETIC-LOCI General Biochemistry Genetics and Molecular Biology Body Mass Index BMI MACROPHAGE INHIBITORY CYTOKINE-1 genomics Humans genetics human Mendelian randomisation RISK General Immunology and Microbiology RECEPTOR General Neuroscience Genetics and Genomics General Medicine ASSOCIATION Mendelian Randomization Analysis Epidemiology and Global Health GDF15 Cardiovascular Diseases MENDELIAN RANDOMIZATION HEART-FAILURE epidemiology 3111 Biomedicine Biomarkers Research Article Genome-Wide Association Study |
| DOI: | 10.17863/cam.88165 |
| Popis: | Funder: Wellcome Trust Funder: Sydäntutkimussäätiö Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW pFDR = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|